Phosphoinositide 3-Kinases



Phosphoinositide 3-Kinases (PI3K) are a family of ubiquitously distributed lipid kinases, that play a critical role in the regulation of numerous cellular processes including cellular growth and morphology, programmed cell death, cell motility and adhesion, mitogenesis and glucose uptake. PI3K generates important second messengers by catalyzing the transfer of the γ-phosphate group of ATP to the D3 position of phosphoinositides. The PI3K preferred substrate is Phosphatidylinositol-4,5-bisphosphate (PIP2), which is converted into phosphatidylinositol-3,4,5-triphosphate (PIP3) upon phosphorylation at the cell membrane. The importance of PI3K is evident in knockout mice studies in which those mice with disruptions of critical PI3K components have significant deficiencies in immune and inflammatory response sometimes resulting in embryonic death. Aberrations in PIP3 levels, either through activation of PI3ks or through inactivation of lipid phosphatase PTEN, occur frequently in numerous forms of cancer, making PI3K an exciting new target to treat cancer among other human diseases.

The Classes of PI3Ks
PI3Ks can be grouped into three distinct classes, Class I-III. Class I PI3Ks, the most well understood and thoroughly explored PI3K class, are composed of a 110kDa catalytic subunit and a 50-100 kDa adaptor subunit. Activation of Class I PI3Ks is controlled by extracellular signaling via receptors with intrinsic tyrosine kinase activity, G protein-linked receptors, or receptors coupled to SRC like protein tyrosine kinases. Class II PI3Ks are relatively poorly understood but are 170-210 kDa and have in vitro substrate specificity toward PtdIns 4-P. Class III PI3Ks depend on Vps15p protein Ser/Thr kinases, which recruits the phosphatidylinositol kinase to late Golgi Compartments.

Class I Subclasses
PI3Ks are activated by extracellular agonists via the translocation of PI3Ks to the plasma membrane for easy access to lipid substrates. Depending on the adaptor proteins involved in the process, Class I PI3Ks are segregated into two subgroups. Those that associate with p85 will be directed to phosphorylated tyrosine motifs (Class IA), while PI3Kγ interacts with trimeric G proteins and the p101 protein (Class IB)

Structure of PI3K
For Full Article, See: The Structure of PI3K

Class I PI3Ks, which are tightly regulated by tyrosine kinases, are composed of an 85kDa regulatory/adapter subunit (p85) and a 110kDa catalytic subunit (p110).

PI3K Activation, Inhibition, and Medical Implications
For Full Article, See: PI3K Activation, Inhibition, & Medical Implications

A number of inhibitors for PI3K have been developed to understand how PI3K is activated and functions. These analysis have massive medical implications for the treatment of Cancer and Diabetes.

Additional 3D Structures
Solved Structures of PI3K

Class I p85α
2iug, 2iuh, 2iui – Crystal Structure of PI3K nSH2 Domain with Peptides 1h9o – Crystal Structure of PI3K SH2 Domain with PDGFR Peptide

2vly - hPI3KI p85α+ABD

3i5s, 3i5r, 1pht - hPI3KI p85α SH3 domain

1pks, 1pkt - hPI3KI p85α SH3 domain - NMR

1fu5, 1fu6 – NMR structure of nSH2 Domain from PI3K

Class I p85β
3mtt – hPI3KI p85β

2kt1 - hPI3KI p85β SH3 domain

3l4q – bPI3KI p85β influenza NS1 protein – bovine

Class II
2wwe – hPI3KIIγ PHOX homology domain

2ar5, 2iwl, 2rea, 2red – hPI3KII PX domain

2b3r - hPI3KII C2 domain

Class III
2x6f, 2x6h, 2x6j, 2x6k – PI3KIII + inhibitors – Drosophila melanogaster

3ls8 – hPI3KIII + inhibitor

3ihy – hPI3KIII

Type I PI3K p110α+p85α
3hhm - hTI-PI3K p110α+p85α SH2 domain + wortmannin

3hiz - hTI-PI3K p110α (mutant) + p85α

2rd0 - hTI-PI3K p110α+p85α

2v1y - bTI-PI3K p110α +h-p85α

Type I PI3K p110α
2enq - hTI-PI3K p110α C2 domain

Type I PI3K p110γ
3lj3 – hTI-PI3K p110γ  + pyrrolopyridine-benzofuran inhibitor

3l54 – hTI-PI3K p110γ + quinoline derivative

3l08 – hTI-PI3K p110γ + GSK2126458

3ibe – hTI-PI3K p110γ + pyrazolopyrimidine

3ene, 2v4l, 2a4z, 2a5u, 1e7u, 1e7v, 1e8w, 1e8y, 1e8z, 1e90, 1e8x – hTI-PI3K p110γ + inhibitor

3dpd – hTI-PI3K p110γ + oxazines inhibitor

3dbs – hTI-PI3K p110γ+ GDC0941

3csf, 3cst – hTI-PI3K p110γ + organourethenium inhibitor

2chw, 2chx, 2chz – hTI-PI3K p110γ + PIK-39 inhibitor

Type I PI3K p110δ
2x38 – hTI-PI3K p110δ + IC87114

2wxf, 2wxg, 2wxh, 2wxi, 2wxj, 2wxk, 2wxl, 2wxm, 2wxn, 2wxo, 2wxp, 2wxq, 2wxr  – hTI-PI3K p110δ + inhibitors

Additional Resources

 * See: Cancer For Additional Proteins involved in the disease.


 * See: Oncogenes for Additional examples of oncogenes and tumor suppressor genes.